4/20/2010 Case 3: Glycogen storage disease type IV (Branching enzyme deficiency) (PAS+)

Presented by: Dr. Mary Fowkes - Mount Sinai Medical Center

Clinical History:

Intrapartum fetal death of a male fetus at 35.1 weeks gestation by dates, 28 year old G1P0 mother.  Maternal history of seizure disorder and brain surgery for arteriovenous malformation in Korea.  Antenatal sonogram at 19 weeks gestation had shown nonspecific echogenic bowel and mild intracranial ventricular dilatation, but TORCH titers and chromosomal studies were normal.  Mother admitted in active labor.  Fetal heart decelerations and bradycardia necessitated emergency C-section, but the fetus was found to be dead upon delivery and could not be resuscitated.  Fetus with no dysmorphic features, congenital malformations, or other significant gross findings, with the exception of cardiac right ventricular dilatation, a frequent accompaniment of fetal death. (Two slides, one H&E, one unstained.)

The brain specimen was very soft at brain cutting, even though gestational age was 36 weeks and the baby had died immediately.  There was focal intraventricular hemorrhage without ventricular distention, and the expected, slightly open operculum.  Cortical development was consistent with 36 gestational weeks but vacuoles were noted in the neurons.  The white matter contained a few microglia and had few myelinated fibers.  The Purkinje cells of the cerebellum contained PAS-positive granulations that disappeared with diastase.  Myelination was decreased in the MLF of the midbrain, being 1+ versus 3+ in the normal infant.  The interstitial nucleus of the MLF had Alcian blue positive intracytoplasmic inclusions.  The psoas muscle was atrophic; it and the liver had Alcian blue-positive inclusions which were also resistant to diastase.  Electron microscopy showed non-membrane-bound granular electron dense inclusions. 

Diagnostic Notes:

The diagnosis was Glycogen storage disease Type IV (Branching Enzyme deficiency), which has diastase-resistant, PAS-positive cytoplasmic inclusions in many organs including neurons, skeletal muscle and placenta.  Some nuclei such as the hypoglossal nucleus accumulate vacuoles, but others will contain granular material.  

There are 13 autosomal recessive glycogen storage diseases (GSD).  GSD4 mimics GSD7.  GSD4 has a classic hepatic form (Andersen's disease) that presents in the first 18 months of life.  There is also a congenital variant with death in early infancy, a juvenile form and a milder non-progressive form.  GSD-IV also has other presentations including cardiomyopathy, arthrogryposis and hydrops fetalis. The dysmyelination seen in this case is not reported, perhaps because the brains are too soft, not taken careful care of and so a decent stain cannot be obtained.

References: 

• Lamperti C et al.  Neuropathological study of skeletal muscle, heart, liver and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene.  J Inher Metabolic Dis 2009 April 8 (epub ahead of print); PMID 19357989. 
  
• Moses SW, Parvari R.  The variable presentations of glycogen storage disease type IV:  a review of clinical, enzymatic and molecular studies.  Curr Molec Med 2002;2(2): 177-188.
  
• Schoser B et al.  Unclassified polysaccharidosis of the heart and skeletal muscle in siblings.  Mol Genet Metabolism 2008;95:52-58.
  
  

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3A

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3B

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